Successes in the treatment of Hodgkin's disease (HD) highlight the long-term consequences of chemotherapy and radiation therapy in the management of this disease. The current inter-group trial reflects the improvement in failure free survival as it pays increasing attention to reducing the late effects of therapy in survivors. The presence of Epstein-Barr virus (EBV) in a significant proportion of HD tumors offers the opportunity to develop the use of virus-specific tumor markers and virus-specific immune therapy. The Eastern Cooperative Oncology Group (ECOG) and Southwestern Oncology Group (SWOG) trial E2496 offers an unparalleled opportunity to address these questions. Through evaluation of this large group of patients, the determination of whether EBV detection in biopsy specimens identifies a poor risk group (particularly in patients over the age of 45 years) should be possible. In addition, the validation of the utility of tissue arrays in the detection of EBV in HD will allow the development of this important and cost-efficient resource. A careful analysis will be performed to determine whether EBV detection studies in tissue arrays or in plasma by real-time PCR yield results parallel to those achieved with detection studies applied to conventional tissue sections. In parallel, the determination of the rate of viral DNA clearance in plasma and the effect of different treatment regimens on this clearance will be performed using real-time PCR. The rate of clearance as well as the persistence of viral DNA in plasma will analyzed to determine if they predict resistant disease or relapse. The relationship between plasma IL-10 levels, IL-10 promoter polymorphisms, and the EBV status of the tumor will be evaluated. Finally, we seek to characterize the cytotoxic T-cell response to EBV antigens expressed in HD (in the context of response to other EBV antigens and antigens from other viruses) and to assess the impact of chemotherapy/radiotherapy on these responses. This work should lay the groundwork for future viral antigen targeted therapies.